Project Summary The global prevalence of Type 2 diabetes (T2D) is a major health concern. There is strong evidence of a genetic basis for human T2D, which follows a polygenic pattern of inheritance. Epidemiological and experimental data suggest that T2D arises from the interplay between genetics and environment (e.g., diet), partly explaining the current diabetes epidemic in a Western environment of excessive energy- dense food consumption. Despite this evidence, the exact nature of gene-diet interactions and underlying causal mechanisms are poorly understood in T2D. One major reason originates from difficulties in accurate dietary assessment in humans, partly due to unreliable methodology such as dietary recalls and questionnaires and individual's subjective perception about food intake. One approach to address this complexity is to use animal models, where the environment can be carefully controlled and modified. TALLYHO (TH) mice encompass many aspects of polygenic human T2D. Our preliminary studies demonstrated that the penetrance of genetic susceptibility to T2D is modulated in TH mice by nutritionally modified diets. Therefore, we hypothesize that (1) the susceptibility of TH mice to T2D is modulated by the combined interaction of diet and genetics which act to alter gene expression in selected tissues and (2) identification of genes whose expression varies with this interaction will enable us to identify T2D susceptibility genetic variants in the TH mouse. To test these hypotheses we will: (1) investigate chronological development of insulin resistance and impairment of insulin secretion in response to diabetogenic diets in TH mice and (2) characterize global gene expression changes caused by diabetogenic diets in TH vs. B6 and F1(FVBxB6) mice and identify the associated genetic variants and pathways by using an integrated functional genomics approach. These studies will identify molecular predictors that connect diet with the etiology of T2D. !